1H-Imidazo[4,5-c]quinolines as kinase inhibitors are described in WO 2003/097641, WO 2005/054237 and WO 2005/054238.
The aim of the present invention is to indicate new compounds which can be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation. The compounds according to the invention are characterised by a powerful inhibitory effect on PDK 1 and a high efficacy against tumour cells, e.g. prostate carcinoma cells, which is mediated through inhibiting PDK 1. As well as the inhibitory effect and cell potency the compounds have good solubility and good selectivity with regard to other signal and cell cycle kinases.
The importance of the PI3K-PDK1-AKT pathway with its frequent aberrations (PTEN loss, PI3K mutation) in the major tumor indications is described in numerous scientific publications (e.g. Samuels et al. 2004; Science; 304: 554; Samuels and Velculescu 2004; Cell Cycle 3; 17-19; Samuels et al. 2005; Cancer Cell; 7: 561-573).
PDK1 alterations (mutations, CN gains) are rarely found isolated from other pathway alterations so that the importance of this target thrives from the fact that it acts as a central signaling node in a frequently altered pathway.
Active PI3K phosphorylates second messengers like Phosphatidylinositol(4,5)-bisphosphate (PtdIns(4,5)P2) to PtdIns(3,4,5)P3, or PtdIns(4)P to PtdIns(3,4,)P2. Such PI3K products recruit AKT and PDK1 kinases via their PH-domains (which bind the PI3 kinase products) to the plasma membrane and allow PDK1 to phosphorylate Thr308 of AKT and thereby activate the enzyme. A second step important for additional AKT activation and/or AKT-substrate selection is mediated by the mTOR/rictor/SIN1 complex which phosphorylates the hydrophobic motif of AKT at Ser473. Activated AKT regulates several other proteins, which are involved in cell proliferation, growth and survival.
Besides AKT, PDK1 has other substrates located in the cytoplasm, e.g. p70S6K, p90RSK, PKCs and SGK, which are also implicated in regulating cell proliferation and cell survival. The activation of these kinases is not dependent on phosphatidylinositols in vitro and functions properly in cells where the PDK1-PH-domain had been destroyed by knock-in mutation (McManus et al. 2004, EMBO J. 23, 2071-2082). For a review on PDK1 mouse mutants also see Bayascas 2008; Cell Cycle 7; 2978-2982).
In conclusion, PDK1 substrates (AKT, p90RSK) act at the crossroad of two important cancer signaling pathways.
A potent and selective inhibitor of the PDK1 kinase is predicted to inhibit tumor growth, delay relapse, or even induce objective tumor responses (i.e. complete or partial tumor shrinkage) in cancer patients.